Potential role of the anterior cingulate cortex in PTSD: Review and hypothesis

Many symptoms of PTSD represent conditioned responses to stimuli associated with a traumatic experiences. In this review, we propose that the anterior cingulate—a brain region that appears to be involved in fear-conditioning—is dysfunctional in PTSD, thus facilitating exaggerated emotional and behavioral responses (hyperarousal) to conditioned stimuli. Preclinical studies suggest that the anterior cingulate may serve a critical gating function in modulating conditioned fear responses. As such, this region would be a key component of a neural circuit involved in the pathophysiology of PTSD. An amygdala-locus coeruleus-anterior cingulate circuit may be consistent with evidence for chronic noradrenergic activation documented in PTSD patients. According to this model, efferent noradrenergic projections from the locus coeruleus may dampen anterior cingulate function. This in turn would allow myriad external or internally driven stimuli to produce the exaggerated emotional and behavioral responses characteristic of PTSD. If confirmed in future research, cingulate dysfunction would have important theoretical and treatment implications. Depression and Anxiety 9:1–14, 1999. Published 1999 Wiley-Liss, Inc.     

Molecular mechanisms of pain in the anterior cingulate cortex

It is well known that peripheral sensory stimuli, including pain, trigger a series of neuronal activities along the somatosensory pathways as well as the neuronal network in the high brain structures. These neuronal activities not only produce appropriate physiological responses but also induce long-term plastic changes in some of the central synapses. It is believed that long-term synaptic changes help the brain to process and store new information. Such learning is critical for animals and humans to gain new knowledge of changing environment, generate appropriate emotional responses, and avoid dangerous stimuli in the future. In the case of permanent injury, however, the brain fails to distinguish the difference between "useful" and painful stimuli. Long-term synaptic changes work against the system and at least in part contribute to chronic pain. In this short article, the possible molecular mechanisms for long-term plasticity within the anterior cingulate cortex (ACC) will be discussed and reviewed, and it is hypothesized that potentiation of excitatory responses within the ACC contributes to chronic pain and pain-related mental disorders.     

Anticipation causes increased blood flow to the anterior cingulate cortex

Increased cerebral blood flow in the anterior cingulate cortex (ACC) has been noted in a range of cognitively demanding tasks studied with PET. A PET study of 10 normal males was carried out using the bolus H₂¹³O intravenous injection technique to examine the effects of anticipation on blood flow to the ACC. In a series of conditions, subjects 1) passively viewed flashing plus signs, 2) noted the occurrence of abstract patterns, 3) named animal pictures, 4) or carried out a semantic judgement on animal pictures. Anticipatory scans were carried out after the subjects were presented with the instructions but before they began the cognitive task, as they were passively viewing plus signs. Significantly increased cerebral blood flow to the ACC was found in all three cognitive tasks when compared with baseline. More importantly, a similar increase was observed in each of the anticipatory states when compared with baseline. When the anticipation scan served as the subtracted baseline for the cognitive task, the increase in blood flow was not significant. This pattern of activity suggests that receiving instructions, preparation, and anticipation of the cognitive task, rather than task-related processing itself, may be responsible for the increased blood flow in the ACC noted in many PET studies of simple cognitive tasks. © 1996 Wiley-Liss, Inc.     

Efferent projections from the anterior thalamic nuclei to the cingulate cortex in the rat

The organization of projections from the anterior thalamic nuclei to the cingulate cortex was analyzed in the rat by the anterograde transport of Phaseolus vulgaris-leucoagglutinin. The rostral part of the anteromedial nucleus projects to layers I, V and VI of the anterior cingulate areas 1 and 2, layers I and III of the ventral orbital area, layers I, V and VI of area 29D of the retrosplenial area, and layers I and V of the caudal part of the retrosplenial granular and agranular areas. In contrast, the caudal part of the anteromedial nucleus projects to layer V of the frontal area 2, and layers I and V of the rostral part of the retrosplenial granular and agranular areas. The interanteromedial nucleus projects to layers I, III and V of the frontal area 2, layer V of the agranular insular area, and layers I, V and VI of area 29D. The anteroventral nucleus projects to layers I and IV of the retrosplenial granular area, whereas the anterodorsal nucleus projects to layers I, III and IV of the same area. Projections from the anteroventral and anterodorsal nuclei were, furthermore, organized such that their ventral parts project to the rostral part of the retrosplenial granular area, whereas their dorsal parts project to the more caudal part. The results suggest that the anterior thalamic nuclei project to more widespread areas and laminae of the cingulate cortex than was previously assumed. The projections are organized such that the anteromedial and interanteromedial nuclei project to layer I and the deep layers of the anterior cingulate and retrosplenial cortex, whereas the anteroventral and anterodorsal nuclei project to the superficial layers of the retrosplenial cortex. These thalamocortical projections may play important roles in behavioral learning such as discriminative avoidance behavior.     

Astrocytic activation in the anterior cingulate cortex is critical for sleep disorder under neuropathic pain

Insomnia, depression, and anxiety disorder are common problems for people with neuropathic pain. In this study, mild noxious heat stimuli increased the duration and number of spontaneous pain‐like behaviors in sciatic nerve‐ligated mice. We used functional magnetic resonance imaging to visualize the increased blood oxygenation level‐dependent signal intensity in the anterior cingulate cortex (ACC) of mice with sciatic nerve ligation under mild noxious stimuli. Such stimuli significantly increased the release of glutamate in the ACC of nerve‐ligated mice. In addition, sciatic nerve ligation and mild noxious stimuli changed the morphology of astrocytes in the ACC. Treatment of cortical astrocytes with glutamate caused astrocytic activation, as detected by a stellate morphology. Furthermore, glutamate induced the translocation of GAT‐3 to astrocyte cell membranes using primary cultured glial cells from the mouse cortex. Moreover, the GABA level at the synaptic cleft in the ACC of nerve‐ligated mice was significantly decreased exposure to mild noxious stimuli. Finally, we investigated whether astrocytic activation in the ACC could directly mediate sleep disorder. With the optogenetic tool channel rhodopsin‐2 (ChR2), we demonstrated that selective photostimulation of these astrocytes in vivo triggered sleep disturbance. Taken together, these results suggest that neuropathic pain‐like stimuli activated astrocytes in the ACC and decreased the extracellular concentration of GABA via an increase in the release of glutamate. Furthermore, these findings provide novel evidence that astrocytic activation in the ACC can mimic sleep disturbance in mice. Synapse 68:235–247, 2014 . © 2014 Wiley Periodicals, Inc.     

Associational connections between the anterior and postetior cingulate gyrus in rabbit

Reciprocal anatomical connections between anterior and posterior divisions of the cingulate gyrus are described for the rabbit. Cells within the anterior limbic and precentral agranular regions of the rostral cingulate gyrus, predominantly from layer V, send afferebts to layer I of posterior cingulate and retrosplenial cortices. Cells from layers II and III of posterior cingulate and from layer V of retrosplenial cortex project rostrally to the anterior limbic and precentral agranular cortices. These data demonstrate the existence of an associational anatomical system connecting anterior and posterior regions of the cingulate gyrus.     

Behavioral conflict, anterior cingulate cortex, and experiment duration: implications of diverging data

We investigated the relationship between behavioral measures of conflict and the degree of activity in the anterior cingulate cortex (ACC). We reanalyzed an existing data set that employed the Stroop task using functional magnetic resonance imaging [Milham et al., Brain Cogn 2002;49:277-296]. Although we found no changes in the behavioral measures of conflict from the first to the second half of task performance, we found a reliable reduction in the activity of the anterior cingulate cortex. This result suggests the lack of a strong relationship between behavioral measurements of conflict and anterior cingulate activity. A concomitant increase in dorsolateral prefrontal cortex activity was also found, which may reflect a tradeoff in the neural substrates involved in supporting conflict resolution, detection, or monitoring processes. A second analysis of the data revealed that the duration of an experiment can dramatically affect interpretations of the results, including the roles in which particular regions are thought to play in cognition. These results are discussed in relation to current conceptions of ACC's role in attentional control. In addition, we discuss the implication of our results with current conceptions of conflict and of its instantiation in the brain. Hum. Brain Mapping 21:96-105, 2004.     

Attenuation of cue-induced cigarette craving and anterior cingulate cortex activation in bupropion-treated smokers: a preliminary study

In untreated smokers, exposure to cigarette-related cues increases both the intensity of cigarette craving and relative glucose metabolism of the perigenual/ventral anterior cingulate cortex (ACC). Given that treatment with bupropion HCl reduces overall cigarette craving levels in nicotine dependent subjects, we performed a preliminary study of smokers to determine if bupropion HCl treatment attenuates cue-induced cigarette craving and associated brain metabolic activation. Thirty-seven, otherwise healthy smokers (20 untreated and 17 who had received open-label treatment with bupropion HCl) underwent two ¹⁸F-fluorodeoxyglucose positron emission tomography scanning sessions in randomized order—one when presented with neutral cues and the other when presented with cigarette-related cues. Bupropion-treated smokers had smaller cigarette cue-induced increases in craving scores on the Urge to Smoke (UTS) Scale and less activation of perigenual/ventral ACC metabolism from the neutral to the cigarette cue scan than untreated smokers. Thus, in addition to its known effects on spontaneous cigarette craving and withdrawal symptoms, bupropion HCl diminishes cue-induced cigarette craving and appears to attenuate cigarette cue-induced ACC activation. These results are consistent with the known effects of bupropion HCl, including its enhancement of catecholaminergic neurotransmission.     

A functional dissociation of conflict processing within anterior cingulate cortex

Goal-directed behavior requires cognitive control to regulate the occurrence of conflict. The dorsal anterior cingulate cortex (dACC) has been suggested in detecting response conflict during various conflict tasks. Recent findings, however, have indicated not only that two distinct subregions of dACC are involved in conflict processing but also that the conflict occurs at both perceptual and response levels. In this study, we sought to examine whether perceptual and response conflicts are functionally dissociated in dACC. Thirteen healthy subjects performed a version of the Stroop task during functional magnetic resonance imaging (fMRI) scanning. We identified a functional dissociation of the caudal dACC (cdACC) and the rostral dACC (rdACC) in their responses to different sources of conflict. The cdACC was selectively engaged in perceptual conflict whereas the rdACC was more active in response conflict. Further, the dorsolateral prefrontal cortex (DLPFC) was coactivated not with cdACC but with rdACC. We suggest that cdACC plays an important role in regulative processing of perceptual conflict whereas rdACC is involved in detecting response conflict.     

Functional connectivity of the anterior cingulate cortex predicts treatment outcome for rTMS in treatment-resistant depression at 3-month follow-up

Background and objectiveRepetitive transcranial magnetic stimulation (rTMS) is a first-line treatment for treatment-resistant depression (TRD). The mechanisms of action of rTMS are not fully understood, and no biomarkers are available to assist in clinical practice to predict response to rTMS. This study aimed to demonstrate that after-rTMS clinical improvement is associated with functional connectivity (FC) changes of the subgenual cingulate cortex (sgACC) and rostral anterior cingulate (rACC), and FC of sgACC and rACC might serve as potential predictors for treatment response.MethodsResting-state functional magnetic resonance imaging (rs-fMRI) data were collected within 1 week before rTMS initiation in 50 TRD patients to predict subsequent response to rTMS on the left dorsolateral prefrontal cortex (DLPFC). Follow-up rs-fMRI was obtained 12 weeks after completion of rTMS and neural correlates of rTMS in sgACC- and rACC-related FC patterns were compared to before rTMS data and with rs-fMRI from healthy participants.ResultsTreatment response was associated with lower FC of sgACC to right DLPFC and higher FC of rACC to left lateral parietal cortex (IPL) measured at baseline. Using sgACC-DLPFC and rACC-IPL connectivity as features, responder-nonresponder classification accuracies of 84% and 76% (end-of-treatment), 88% and 81% (3-month follow-up), respectively were achieved. Longitudinal rs-fMRI data analyses revealed that the hyperconnectivity between sgACC and visual cortex was normalized to a level which was comparable to that of healthy participants.ConclusionsBrain activity patterns in depression are predictive of treatment response to rTMS, and longitudinal change of brain activity in relevant brain circuits after rTMS is associated with treatment response in depression. Target engagement paradigms may offer opportunities to increase the efficacy of rTMS in TRD by optimal selection of patients for treatment.Trial registrationClinicalTrials.gov Identifiers: NCT01887782 and NCT02800226.     

Inflammatory bowel disease: perspectives from cingulate cortex in the first brain

The article by Agostini et al. (2013) in this issue of Neurogastroenterology and Motility evaluated patients with Crohn’s disease (CD) for volumetric changes throughout the brain. They observed decreased gray matter volumes in dorsolateral prefrontal cortex and anterior midcingulate cortex (aMCC) and disease duration was negatively correlated with volumes in subgenual anterior cingulate (sACC), posterior MCC (pMCC), ventral posterior cingulate (vPCC), and parahippocampal cortices. As all patients were in remission and suffered from ongoing abdominal pain, this study provides a critical link between forebrain changes and abdominal pain experience independent of active disease and drug treatment. The aMCC has a role in feedback‐mediated decision making and there are specific cognitive tasks that differentiate aMCC and pMCC that can be used to evaluate defects in CD. The sACC is an important area as it has impaired functions in major depression. As depressive symptoms are a feature in a subset of patients with active inflammatory diseases including IBD, treatment targeting this subregion should prove efficacious. Finally, vPCC has a role in ongoing self‐monitoring of the personal relevance of sensory stimuli including visceral signals via sACC. This pathway may be interrupted by vPCC atrophy in CD. Cingulate atrophy in CD leads to targeting chronic pain and psychiatric symptoms via cingulate‐mediated therapies. These include psychotherapy, guided imagery and relaxation training, analgesic dosages of morphine or antidepressants, and hypnosis. Thus, a new generation of novel treatments may emerge from drug and non‐traditional therapies for CD in this formative area of research.     

Activation of the caudal anterior cingulate cortex due to task‐related interference in an auditory Stroop paradigm

Successful information processing requires the focusing of attention on a certain stimulus property and the simultaneous suppression of irrelevant information. The Stroop task is a useful paradigm to study such attentional top‐down control in the presence of interference. Here, we investigated the neural correlates of an auditory Stroop task using fMRI. Subjects focused either on tone pitch (relatively high or low; phonetic task) or on the meaning of a spoken word (high/low/good; semantic task), while ignoring the other stimulus feature. We differentiated between task‐related (phonetic incongruent vs. semantic incongruent) and sensory‐level interference (phonetic incongruent vs. phonetic congruent). Task‐related interference activated similar regions as in visual Stroop tasks, including the anterior cingulate cortex (ACC) and the presupplementary motor‐area (pre‐SMA). More specifically, we observed that the very caudal/posterior part of the ACC was activated and not the dorsal/anterior region. Because identical stimuli but different task demands are compared in this contrast, it reflects conflict at a relatively high processing level. A more conventional contrast between incongruent and congruent phonetic trials was associated with a different cluster in the pre‐SMA/ACC which was observed in a large number of previous studies. Finally, functional connectivity analysis revealed that activity within the regions activated in the phonetic incongruent vs. semantic incongruent contrast was more strongly interrelated during semantically vs. phonetically incongruent trials. Taken together, we found (besides activation of regions well‐known from visual Stroop tasks) activation of the very caudal and posterior part of the ACC due to task‐related interference in an auditory Stroop task. Hum Brain Mapp, 2009. © 2009 Wiley‐Liss, Inc.     

Elevation of cell adhesion molecule immunoreactivity in the anterior cingulate cortex in bipolar disorder.

BACKGROUND: Neuroimaging reports of increases in signal hyperintensities in white and deep gray matter and other work indicate that there might be an inflammatory response in affective disorders. METHODS: The microvascular immunoreactivity of intercellular adhesion molecule-1 and vascular cell adhesion molecule-1 was measured with image analysis in postmortem tissue from the anterior cingulate cortex (ACC) and dorsolateral prefrontal cortex (DLPFC) from 15 unipolar and 15 bipolar subjects and compared with each other and with 15 subjects with schizophrenia and 15 control subjects. RESULTS: Intercellular adhesion molecule-1 immunoreactivity in gray and white matter of the ACC in bipolar subjects was increased compared with control subjects (gray: p =.001; white: p <.001) and schizophrenic subjects (gray: p =.016; white: p =.025) and modestly increased in white matter compared with unipolar subjects (p =.049). No such differences were found in the DLPFC. CONCLUSIONS: These findings are consistent with the presence of an inflammatory response in the ACC in bipolar disorder.     

Inhibitory cartridge synapses in the anterior cingulate cortex of schizophrenics

Summary. Axon cartridges are the specific terminal structures of GABAergic inhibitory chandelier interneurons. Cartridges form axo-axonal synapses with local projection neurons, thus modulating the neuronal output of diverse brain areas. In order to examine the distribution of cartridges, the anterior cingulate cortices from the brains of schizophrenic patients and control persons were examined with an antibody against parvalbumin. Axon cartridges were mainly located in layers V and VI. In our study, schizophrenic patients showed a significantly higher density of axon cartridges than controls. These findings add new evidence for disturbances of the circuitry of the anterior cingulate cortex in schizophrenia implicating that there may be an elevated inhibitory influence on the cortical output of this brain region. Received September 21, 1998; accepted December 22, 1998     

The anterior insular and anterior cingulate cortices in emotional processing for self-face recognition

Individuals can experience embarrassment when exposed to self-feedback images, depending on the extent of the divergence from the internal representation of the standard self. Our previous work implicated the anterior insular cortex (AI) and the anterior cingulate cortex (ACC) in the processing of embarrassment; however, their exact functional contributions have remained uncertain. Here, we explored the effects of being observed by others while viewing self-face images on the extent of embarrassment, and the activation and connectivity patterns in the AI and ACC. We conducted functional magnetic resonance imaging hyperscanning in pairs of healthy participants using an interaction system that allowed an individual to be observed by a partner in real time. Being observed increased the extent of embarrassment reported when viewing self-face images; a corresponding increase in self-related activity in the right AI suggested that this region played a direct role in the subjective experience. Being observed also increased the functional connectivity between the caudal ACC and prefrontal regions, which are involved in processing the reflective self. The ACC might therefore serve as a hub, integrating information about the reflective self that is used in evaluating perceptual self-face images.     

Increased anterior cingulate cortex and hippocampus activation in Complex PTSD during encoding of negative words

Post-traumatic stress disorder (PTSD) is associated with impaired memory performance coupled with functional changes in brain areas involved in declarative memory and emotion regulation. It is not yet clear how symptom severity and comorbidity affect neurocognitive functioning in PTSD. We performed a functional magnetic resonance imaging (fMRI) study with an emotional declarative memory task in 28 Complex PTSD patients with comorbid depressive and personality disorders, and 21 healthy non-trauma-exposed controls. In Complex PTSD patients—compared to controls—encoding of later remembered negative words vs baseline was associated with increased blood oxygenation level dependent (BOLD) response in the left ventral anterior cingulate cortex (ACC) and dorsal ACC extending to the dorsomedial prefrontal cortex (dmPFC) together with a trend for increased left hippocampus activation. Patients tended to commit more False Alarms to negative words compared to controls, which was associated with enhanced left ventrolateral prefrontal and orbitofrontal cortex (vlPFC/OFC) responses. Severity of child abuse was positively correlated with left ventral ACC activity and severity of depression with (para) hippocampal and ventral ACC activity. Presented results demonstrate functional abnormalities in Complex PTSD in the frontolimbic brain circuit also implicated in fear conditioning models, but generally in the opposite direction, which may be explained by severity of the trauma and severity of comorbid depression in Complex PTSD.     

Protein synthesis in the posterior cingulate cortex in Alzheimer's disease

Background: Neuroimaging studies using ¹⁸F‐fluoro‐2‐deoxy‐D‐glucose positron emission tomography (FDG‐PET) and single photon emission computed tomography (SPECT) have shown that the posterior cingulate cortex (PCC) is the primary and most prominent area of cerebral metabolic and perfusional decrement in early Alzheimer's disease (AD). We carried out the present preliminary study to investigate whether a decline of cerebral blood flow (CBF) in the PCC in early to moderate AD was accompanied with that of cerebral protein synthesis (CPS). Methods: We carried out both N‐isopropyl‐p‐[123I] iodoamphetamine SPECT (IMP‐SPECT) and L‐[methyl‐11C] methionine positron emission tomography (MET‐PET) in eight AD patients with apolipoprotein E epsilon 4 allele in the early to moderate stage. We also carried out IMP‐SPECT in eight healthy controls (HC). We located 32 regions of interest (ROI), and values of regional MET or IMP uptakes were averaged in five regions; the frontal lobe (FL), the parietal lobe (PL), the medial temporal lobe (MTL), PCC and the occipital lobe. Furthermore, the values in the FL, PL, MTL and PCC were divided by values in the occipital areas, and normalized values of regional CBF (rCBF) and CPS (rCPS) were calculated. Then, the rCBF in the FL, PL, MTL and PCC were compared between AD and HC. In addition, the rCBF and rCPS were compared in the FL, PL, MTL and PCC of AD. Results: The rCBF in the PCC, but not in the other three regions, was significantly lower in AD than in HC. The rCBF was significantly lower than rCPS in the PCC, but rCBF and rCPS were comparable in the other three regions in AD. Conclusions: The CBF reduction in the PCC in AD was partly caused by neuronal loss in the PCC and partly supported the hypothesis that CBF reduction in the PCC was a result of functional deafferentation by neural degeneration in areas other than the PCC.     

The anterior cingulate ERK pathway contributes to regulation of behavioral excitement and hedonic activity

Objectives:  Several intracellular signaling cascades, such as the extracellular signal-regulated kinase (ERK), Wnt-signaling/GSK-3, PLC/PKC, and PI3K pathways, have been shown to be affected directly or indirectly by mood stabilizers. Clinical imaging studies reveal that mood disorders are associated with structural and/or metabolic changes in specific brain regions such as the anterior cingulate cortex (ACC). Here we investigated the extent to which perturbation of one of the affected pathways, the ERK pathway, in the ACC influences affective-related behavior.
Methods:  The regional perturbation was induced by two means: local continuous infusion of PD98059, an ERK pathway inhibitor, and microinjection of a lentiviral-mediated gene delivery system encoding functional negative ERK1. The outcomes were monitored with a battery of affective-related tests similar to those used in several previous studies.
Results:  Compared to their respective controls, rats infused with PD98059 or injected with the lentiviral negative ERK1 construct displayed hyperactivities in multiple tests, exhibited preferentially more open-arm activity in the elevated-plus-maze test, consumed more sweetened liquid in a saccharin preference test, and showed heightened response to amphetamine.
Conclusions:  These data support a role for the ACC ERK pathway in the regulation of affective-related behaviors. However, the medial prefrontal cortex (mPFC) comprises at least three other regions that will need to be similarly examined before specific roles of the ACC ERK pathway can be definitively attributed to affective behaviors. Additionally, responses of other signaling pathways to mood stabilizers in these mPFC regions, as well as the limbic regions to which they project, will be important to examine.     

Magnetic resonance spectroscopy of the anterior cingulate cortex in eating disorders

The anterior cingulate cortex plays a key role in eating disorders (ED), but it remains an open question whether there are deviations of the neurochemistry of this region in patients with ED. Seventeen adult female patients with ED (10 with bulimia nervosa, 7 with anorexia nervosa) were compared to 14 matched female healthy controls using single voxel magnetic resonance spectroscopy of the anterior cingulate cortex. Group comparisons did not reveal any differences between patients and controls, but a positive correlation between glutamate and myo-inositol signals with “drive for thinness” in patients with bulimia nervosa was found in exploratory correlation analyses.     

Real time fMRI feedback of the anterior cingulate and posterior insular cortex in the processing of pain

Self‐regulation of brain activation using real‐time functional magnetic resonance imaging has been used to train subjects to modulate activation in various brain areas and has been associated with behavioral changes such as altered pain perception. The aim of this study was to assess the comparability of upregulation versus downregulation of activation in the rostral anterior cingulate cortex (rACC) and left posterior insula (pInsL) and its effect on pain intensity and unpleasantness. In a first study, we trained 10 healthy subjects to separately upregulate and downregulate the blood oxygenation level‐dependent response in the rACC or pInsL (six trials on 4 days) in response to painful electrical stimulation. The participants learned to significantly downregulate activation in pInsL and rACC and upregulate pInsL but not rACC. Success in the modulation of one region and direction of the modulation was not significantly correlated with success in another condition, indicating that the ability to control pain‐related brain activation is site‐specific. Less covariation between the areas in response to the nociceptive stimulus was positively correlated with learning success. Upregulation or downregulation of either region was unrelated to pain intensity or unpleasantness; however, our subjects did not learn rACC upregulation, which might be important for pain control. A significant increase in pain unpleasantness was found during upregulation of pInsL when covariation with the rACC was low. These initial results suggest that the state of the network involved in the processing of pain needs to be considered in the modulation of pain‐evoked activation and its behavioral effects. Hum Brain Mapp 35:5784–5798, 2014. © 2014 Wiley Periodicals, Inc.